Bridging Gaps in the Multidimensional Assessment and Management of Overlapping Symptoms in Multiple Sclerosis and Functional Motor Disorders: Prevalence and Rehabilitation Effectiveness

This multicenter prospective study is conducted at two tertiary multiple sclerosis (MS) centers in Italy and uses a sequential design combining an observational diagnostic phase with a nested randomized rehabilitation trial. The study addresses the clinical difficulty of distinguishing inflammatory MS relapse from functional motor symptoms in people with established MS. Functional motor disorder (FMD) may coexist with MS and produce weakness, tremor, gait disturbance, postural instability, or other motor manifestations that resemble relapse or progression. Misclassification may result in unnecessary investigations or anti-inflammatory treatment and may delay access to mechanism-specific rehabilitation.

In Part A, 192 consecutive adults with MS presenting with self-reported acute neurological symptom worsening within the previous 30 days will undergo a standardized, cross-sectional multidimensional assessment. Part A is observational, and no study intervention will be assigned. The assessment will integrate neurological examination, positive clinical signs of FMD, functional and patient-reported evaluations, gait and balance measures, and laboratory or magnetic resonance imaging findings obtained as part of routine clinical care when clinically indicated.

Participants will be classified as having a true MS relapse, FMD-MS overlap or functional pseudorelapse, or another clinically relevant explanation for symptom worsening. A true relapse will be defined according to the occurrence of new or worsening neurological symptoms lasting at least 24 hours in the absence of fever, active infection, trauma, or another acute medical cause. FMD-MS overlap will be established using positive signs of functional motor dysfunction together with applicable DSM-5 and Gupta-Lang criteria. Complex or borderline cases may undergo central diagnostic review to improve consistency between centers. Routine clinical decisions regarding investigations and management of the presenting episode will remain under the responsibility of the treating physician.

Part A will estimate the prevalence of FMD-MS overlap in this clinical population and characterize the multidimensional features associated with the different diagnostic classifications. The planned sample of 192 participants allows for incomplete assessments while providing approximately ±5% precision around an expected prevalence of 13%.

In Part B, participants identified during Part A as having confirmed FMD-MS overlap will be evaluated for suitability for the rehabilitation trial. Approximately 26 participants are expected to proceed to Part B. These participants form a subgroup of the 192 participants enrolled in Part A and are therefore not additional to the overall study enrollment. Participants who do not proceed to Part B will complete their study participation after Part A, while their data will remain included in the observational analyses.

Part B is a pilot, randomized, assessor-blinded, parallel-group, active-controlled trial. After confirmation of eligibility and completion of baseline assessments, participants will be randomized in a 1:1 ratio to targeted FMD-specific multidisciplinary rehabilitation or conventional MS rehabilitation. The allocation sequence will be computer-generated and concealed until treatment assignment. Participants and treating therapists cannot be blinded because of the nature of the interventions; however, outcome assessments will be conducted by evaluators unaware of treatment allocation.

The experimental programme combines a short, intensive in-person intervention with continued home-based self-management and structured telemedicine support. It is based on FMD-specific principles, including explanation of functional symptom mechanisms, identification and therapeutic use of positive functional signs, movement retraining through attentional redirection, and restoration of more automatic motor control. The active comparator consists of conventional MS neurorehabilitation addressing mobility, strength, gait, balance, endurance, fatigue management, and functional independence, without protocolized FMD-specific techniques.

Part B is intended to evaluate the feasibility, safety, and preliminary clinical effects of the targeted programme rather than provide definitive confirmatory evidence of efficacy. Analyses will primarily follow the intention-to-treat principle, with complementary per-protocol analyses where appropriate. Given the pilot sample size, interpretation will emphasize recruitment, adherence, retention, data completeness, outcome variability, effect estimates, and confidence intervals. Together, the two study parts are designed to establish the clinical relevance of FMD-MS overlap and generate evidence needed to plan a larger definitive rehabilitation trial.